Telomerase and its potential for therapeutic intervention

Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation--a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed.     

RNAi: gene-silencing in therapeutic intervention

Several rapidly developing RNA interference (RNAi) methodologies hold the promise to selectively inhibit gene expression in mammals. RNAi is an innate cellular process activated when a double-stranded RNA (dsRNA) molecule of greater than 19 duplex nucleotides enters the cell, causing the degradation of not only the invading dsRNA molecule, but also single-stranded (ssRNAs) RNAs of identical sequences, including endogenous mRNAs. As such, RNAi technology is currently being evaluated not only as an extremely powerful instrument for functional genomic analyses, but also as a potentially useful method to develop highly specific dsRNA based gene-silencing therapeutics.     

Inflammatory bone loss: pathogenesis and therapeutic intervention

Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.     

Targeting Pyk2 for therapeutic intervention

Importance of the field: The focal adhesion tyrosine kinases FAK and Pyk2 are uniquely situated to act as critical mediators for the activation of signaling pathways that regulate cell migration, proliferation and survival. By coordinating adhesion and cytoskeletal dynamics with survival and growth signaling, FAK and Pyk2 represent molecular therapeutic targets in cancer as malignant cells often exhibit defects in these processes.

Areas covered in this review: This review examines the structure and function of the focal adhesion kinase Pyk2 and intends to provide a rationale for the employment of modulating strategies that include both catalytic and extra-catalytic approaches that have been developed in the last 3 – 5 years.

What the reader will gain: Targeting tyrosine kinases in oncology has focused on the ATP binding pocket as means to inhibit catalytic activity and downregulate pathways involved in tumor invasion. This review discusses the available catalytic inhibitors and compares them to the alternative approach of targeting protein–protein interactions that regulate kinase activity.

Take home message: Development of specific catalytic inhibitors of the focal adhesion kinases has improved but significant challenges remain. Thus, approaches that inhibit the effector function of Pyk2 by targeting regulatory modules can increase specificity and will be a welcome asset to the therapeutic arena.     

Interleukin-5, eosinophilic diseases and therapeutic intervention

Interleukin 5 (IL-5) is the key cytokine in an eosinophil's life span: it supports eosinophilopoiesis and eosinophil differentiation, contributes to eosinophil migration, tissue localisation and function, and prevents eosinophil apoptosis. Given the likely role of eosinophils in chronic inflammatory diseases, a lot of research over the past decade was aimed at antagonising IL-5 function. It appears from recent studies that, although this can easily be achieved in vitro, blocking IL-5 function in vivo is much more difficult than originally anticipated. Here, we review the current status of IL-5 and IL-5 receptor research, with emphasis on strategies to interfere with IL-5 function.     

Osteoarthritis: pathobiology-targets and ways for therapeutic intervention

Osteoarthritis is first and foremost the ongoing destruction of the articular cartilages of joints. Therefore, the extracellular matrix and the cells of the articular cartilages are the primary targets of osteoarthritis therapy. This tries to inhibit enzymatic destruction of the extracellular cartilage matrix as well as the modification of the cellular phenotype of the chondrocytes: cell degeneration and cell death are alongside anabolic activation and stabilization of the cellular phenotype of major interest. However, apart from the cartilage and its cells, other tissues of the joints are also important for the symptoms of the disease, which basically all originate outside the articular cartilage. In addition, changes in the subchondral bone as well as the synovial capsule and membrane are important at least for the progression of the disease process. All the named tissues offer different directions and ways for therapeutic intervention.     

Harnessing nanomedicine for therapeutic intervention in glioblastoma

ABSTRACT

Introduction: Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients.

Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies.

Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM     

Tumor vasculature as target for therapeutic intervention

Importance of the field: Solid tumors rely on efficient oxygen and nutrients transport for their growth, development and survival. Many tumors can stimulate new blood vessel formation. Because this angiogenic vasculature is aberrant from normal host vasculature, several strategies have been explored that specifically target tumor blood vessels.

Areas covered in this review: Over the past decade, many molecules that act on tumor vasculature have been identified. They can be divided into three groups based on their mechanism of action: i) antiangiogenic molecules cause tumor growth arrest; ii) vasoactive agents induce hyperabnormalization of the tumor vasculature, improving conventional drug accumulation in the tumor; iii) vascular disrupting agents that cause blood vessel congestion, resulting in massive secondary tumor cell necrosis. Many investigational drugs from these classes are currently being evaluated to assess their role in tumor therapy.

What the reader will gain: The underlying principle of each of the strategies is discussed, and the (pre)clinical results of the investigational drugs in this class are highlighted.

Take home message: To fully exploit the therapeutic potential of these drugs, it appears necessary to combine them with conventional anticancer agents, improve their selectivity for tumor vasculature, and develop biomarkers that predict the tumor sensitivity for these vascular strategies.     

Molecular mechanisms of diabetic nephropathy and its therapeutic intervention

Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large landmark clinical studies have shown that intensive glucose control reduces the risk of the development and progression of diabetic nephropathy, and the blockade renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. However, diabetic nephropathy remains the leading cause of end-stage renal failure in developed countries. Therefore, to develop novel therapeutic strategies that specifically target diabetic nephropathy may be helpful for most patients with diabetes. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), and activation of the RAS and protein kinase C (PKC), elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. This article summarizes the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions that may prevent this devastating disorder even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.     

胎儿室上性心动过速的超声心动图诊断及治疗干预评价

目的胎儿心动过速的宫内胎儿超声心动图诊断及干预治疗室上性心动过速(SVT)评价。方法对已检出的1 911名心律失常胎儿中的126例快速心律失常者,分为窦性心动过速、SVT、SVT合并心衰3组,对后两组胎儿进行宫内地高辛转律治疗。结果胎儿心动过速126例(心率≥180bpm)中SVT 29例(含房颤、房扑10例),窦性心动过速97例。SVT组中合并复杂先天性心脏病者7例、胎儿水肿5例。合并先天性心脏病7例均于检查后中止妊娠,其余22例行常压氧治疗或经胎盘给药,首选药物为地高辛。新生儿随访期最长者16个月,头颅CT、超声心动图等各项生理指标均正常。结论胎儿超声心动图是目前惟一可迅速检出胎儿心律失常并明确性质的诊断手段,且重复性好。地高辛经胎盘治疗可有效转律并同时控制胎儿心衰减轻水肿且无致畸作用。     

Multiple sclerosis: emerging opportunities for therapeutic intervention

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system of unknown etiology. Two of the major therapies for the treatment of MS, interferon-beta and glatiramer acetate, show only limited evidence that long-term treatment slows disability. There is a great need for new drugs that will halt, reverse, and prevent the development of MS. This article reviews therapies currently in use and describes innovative strategies being developed to alter the disease course. New technologies in gene expression profiling offer hopeful directions toward the design of successful drug therapies and diagnostic testing for MS. Additionally, the new fields of genomics and proteomics offer the promise of novel treatments, and should help to reveal the mechanisms of disease initiation and pathological progression.     

心衰治疗靶点与干预研究进展

随着对心衰发病、进程以及恶化病理生理过程了解的不断深入,心衰新靶点的干预正在成为治疗心衰的希望。文中综述了心肌肥厚过程中包括钙调神经磷酸酶(CaN)、G蛋白、糖原合酶激酶3(GSK3)、肌细胞增强因子2(MEF2)、过氧化物酶体增生激活受体(PPAR)、小G蛋白(smallG protein)、Na+/H+交换体(NHE)、亚细胞器(subcellular organelles)的治疗靶点,以及天冬氨酸特异性半胱氨酸蛋白酶(Caspase)、核酸内切酶、凋亡调节因子等细胞凋亡治疗靶点与干预,同时,也综述了内皮素及受体、炎性因子及贫血治疗新靶点的干预药物、干预措施及机制,为心衰治疗、新药研发提供思路。     

经桡动脉和经股动脉途径行冠状动脉介入诊治的疗效比较

目的探讨和比较经桡动脉途径和股动脉途径行冠状动脉介入治疗的疗效。方法 2010年6月～2012年6月本院诊治60例急性冠脉综合征患者,根据穿刺途径将其分为桡动脉组和股动脉组,每组各30例,对两组患者的穿刺时间、住院时间以及术后并发症等方面进行观察和比较。结果两组冠状动脉介入诊疗时间无明显差别,与股动脉组相比,桡动脉组的穿刺时间、住院时间明显缩短,P<0.05。与股动脉组相比,桡动脉组术后出现并发症的发生率明显降低,P<0.05。结论相对于股动脉途径,经桡动脉行冠状动脉介入治疗的术后并发症相对较少,并且住院时间相对较短,大大增加了患者的舒适度,更容易被患者及其家属接受。     

Mitochondrial pathology in Parkinson's disease and implications for therapeutic intervention

Although the ultimate origin and role of mitochondrial pathology in Parkinson's disease (PD) remains controversial, accumulating data suggest that mitochondrial dysfunction is genetic and plays an important role in neurodegeneration. PD mitochondria display abnormal electron transport chain activity, increased reactive oxygen species generation, and abnormal calcium handling. These abnormalities arise, at least in part, from information encoded by mitochondrial DNA. These processes are implicated in current models of neuronal death and validate ongoing efforts to develop mitochondrial‐level pharmacologic interventions for the treatment of this disease.<n>Drug Dev. Res. 46:44–50, 1999. © 1999 Wiley‐Liss, Inc.     

The parathyroid hormone receptorsome and the potential for therapeutic intervention

The parathyroid hormone 1 receptor (PTH1R) is activated by parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP), hormones that mediate mineral ion homeostasis and tissue development, respectively. These diverse actions mediated by one receptor are likely due to the formation of cell-specific receptorsome complexes with cytosolic constituents. Through the second and third intracellular loops, the PTH1R couples to several G protein subclasses, including Gs, Gq/11, Gi/o and G12/13, resulting in the activation of many pathways. The PTH1R carboxy-terminal tail directs interactions with a plethora of binding partners. The WD1 and WD7 repeats of the G protein β subunit directly bind to a novel interaction domain located near the amino-terminal end of the PTH1R carboxy-terminal tail. This Gβγ binding site likely contributes to the promiscuous G protein coupling displayed by the PTH1R. Partially overlapping this site is an EF-hand binding domain that directs interactions with calpain, a calcium-activated protease, and calmodulin, a ubiquitous calcium sensor. A lysine-arginine-lysine motif located on the juxtamembrane region of the carboxy-terminal tail mediates interactions with ezrin, an actin-membrane cross-linking protein. The C-terminus of the PTH1R binds to the sodium-hydrogen regulatory factors (NHERFs) via a PDZ domain-mediated interaction, an association that influences signaling and membrane anchoring. Through direct interactions with ezrin and NHERF-1, a PTH1R receptorsome complex exists on apical membranes of the proximal tubule, an assembly that directs PTH-mediated regulation of phosphate transport. Targeting the PTH1R receptorsome will likely enhance therapies directed towards the treatment of osteoporosis and enhancing the hematopoietic stem cell niche.